Powdery preparation for nasal administration

ABSTRACT

According to the present invention, a powdery preparation for nasal administration comprising a physiologically active substance, a non-water-absorbing and hardly water-soluble powder(s) and one or two selected from the group consisting of a mucolytic agent and a nonionic surfactant is provided.

TECHNICAL FIELD

The present invention relates to a powdery preparation for nasaladministration, and to a powdery preparation for nasal administrationwhich comprises a physiologically active substance, anon-water-absorbing and hardly water-soluble powder(s), and one or twoselected from the group consisting of a mucolytic agent(s) and anonionic surfactant(s), in which absorption of the physiologicallyactive substance at a nasal mucous membrane is improved.

BACKGROUND ART

Physiologically active peptides such as hormone, cytokine, etc. have animportant role in a living body, and it has frequently been carried outto use a physiologically active peptide itself as a medicinemanufactured by mass production, or to use a physiologically activepeptide as a medicine by structurally changing and modifying it by meansof genetic engineering or protein synthesis.

However, the physiologically active peptide involves a risk that it isdecomposed by digestive juices or enzymes in digestive tract or at thewall of the digestive tract when it is administered orally. Also, evenwhen it is absorbed by the digestive tract, after the absorption, itcirculates in the whole body after passing firstly through liver, sothat there are problems that there is a possibility that it isdecomposed in the liver (first-pass effect by the liver), and thephysiologically active peptide with high hydrophilicity is a polymer andhas high polarity whereby it is generally scarcely absorbed by a mucousmembrane of the digestive tract.

Thus, to attain sufficient medicinal effects of the physiologicallyactive peptide, it is not generally administered orally but isintroduced in the form of injection subcutaneously, intramuscularly ordirectly into blood circulation. However, administration by an injectionrequires a patient's attendance at a hospital and is painful, so thatthe administration at home or without pain is desired.

As one of the administration form, it has been proposed to carry outnasal administration which is to administer a medicine to nasal mucousmembrane (particularly, mucous membranes of concha nasalis superior,concha nasalis media, concha nasalis inferior) where epidermis cellshaving cilia covered by mucus, and basement membrane, and vascularsystem is developed at the bottom portion. However, the epidermis cellsare closely bound by conjugant so that permeability of thephysiologically active peptide having a large molecular weight, etc. islow and various preparations have been proposed to improve permeability.

For example, in Japanese Patent Publication No. Sho. 62-42888, there isdescribed a composition for powdery preparation for nasal administrationcomprising physiologically active polypeptides and an agent (crystallinecellulose, etc.) which is water-absorbing and hardly water-soluble, andin Japanese Unexamined Patent Publication No. Hei. 8-27031, there isdisclosed a composition for nasal absorption in which a physiologicallyactive substance having a molecular weight of 40000 or less is uniformlydispersed, attached and bound to powdery or crystalline polyvalent metalcompound carrier (aluminum compound, calcium compound, etc.) having anaverage particle diameter of 250 μm or less.

In summary collection of 27th Formulation Seminar of The PharmaceuticalSociety of Japan, pp. 19-20, there has been reported that improvement inbioavailability through nasal administration had been observed when ahardly soluble powder such as calcium carbonate, ethyl cellulose, talc,barium sulfate, etc. had been used as a pharmaceutical carrier withregard to a water-soluble compound having a molecular weight of 1000 ormore.

Also, in Japanese Unexamined Patent Publication No. Hei. 11-322582, acomposition for nasal administration in which a medicine is uniformlydispersed and adsorbed on a primary granulated carrier ofmicrocrystalline, etc. (calcium carbonate powder, etc.) having a numberof cavities on the surface thereof has been disclosed.

Moreover, in Japanese Unexamined Patent Publication No. 2002-128704,there is described a nasal administration type preparation comprising aphysiologically active substance, a carrier and an absorption promoterin living body (highly substituted hydroxypropyl cellulose,micro-crystalline cellulose), and as the carrier, a water-solublepolymer compound (cellulose derivatives such as crystalline cellulose,methyl cellulose, ethyl cellulose, carboxymethyl cellulose, etc.) hasbeen mentioned.

Also, in Japanese Unexamined Patent Publication No. Sho. 59-130820, anaqueous solution for nasal administration has been disclosed in whichPolysorbate 80 which is a nonionic surfactant is added to calcitonintogether with acetic acid and sodium acetate, and they are dissolved inpurified water.

In Pharmaceutical Research, vol. 7, No. 7, pp. 772-776 (1990), there hasbeen reported that when N-acetyl-L-cysteine, etc. are added with highconcentrations to an aqueous buffer containing human growth hormone, andthe preparation is nasally administered to rats, bioavailability isslightly improved.

However, these preparations for nasal administration have the problemthat improvement in absorption is not sufficient.

DISCLOSURE OF THE INVENTION

The present invention is to provide a powdery preparation for nasaladministration which comprises a physiologically active substance, anon-water-absorbing and hardly water-soluble powder(s), and one or twoselected from the group consisting of a mucolytic agent(s) and anonionic surfactant(s), and by the nasal administration, a sufficientconcentration in blood stream for the activity of the physiologicallyactive substance in a living body can be accomplished.

The present inventors have found that a non-water-absorbing and hardlywater-soluble powder(s) and at least one selected from the groupconsisting of a mucolytic agent(s) and a nonionic surfactant(s) areadded to the physiologically active substance, and the resulting productis administered nasally, then, the nasal absorption of thephysiologically active substance can be markedly improved whereby thepresent invention has been accomplished.

That is, the present invention relates to a powdery preparation fornasal administration which comprises a physiologically active substance,a non-water-absorbing and hardly water-soluble powder(s), and one or twoselected from a mucolytic agent(s) and a nonionic surfactant(s).

When the powdery preparation for nasal administration of the presentinvention is sprayed/inhaled into nasal cavity, due to the presence ofthe non-water-absorbing and hardly water-soluble powder(s), thephysiologically active substance and the mucolytic agent and/or thenonionic surfactant are attached to mucous membrane of the nasal cavityand retained, and yet the non-water-absorbing and hardly water-solublepowder(s) does/do not absorb mucus of the nasal mucous membrane, so thatthe physiologically active substance and the mucolytic agent- and/or thenonionic surfactant are dissolved in a minute amount of the mucus,whereby the physiologically active substance and the mucolytic agent-and/or the nonionic surfactant cause locally high concentrationsolution. In such a state, by utilizing concentration gradient of thephysiologically active substance, and according to the action of themucolytic agent- and/or the nonionic surfactant dissolved at a highconcentration, absorption property itself through the nasal mucousmembrane is locally improved and the physiologically active substancecan reach from the nasal mucous membrane the blood vessel systemexisting under the membrane with good efficiency, whereby nasalabsorption of the physiologically active substance can be promoted.

Also, a non-water-absorbing and hardly water-soluble powder(s) does/donot itself absorb a medicine dissolved in the nasal cavity, so that anavailability of the medicine for absorption is not lowered.

And yet, the powdery preparation for nasal administration of the presentinvention acts on the nasal mucous membrane locally and scatteringly, sothat it does not act on the whole nasal mucous membrane as in the liquidpreparation for nasal administration, whereby it causes less adverseeffects on the nasal mucous membrane.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows plasma salmon calcitonin (hereinafter referred to as SCT)concentration versus time profile when a powder for administrationcontaining SCT, N-acetyl-L-cysteine (hereinafter referred to as NAC) andethyl cellulose (hereinafter referred to as EC) is nasally administeredto rats.

FIG. 2 shows plasma SCT concentration versus time profile when a powderfor administration containing SCT, NAC and cellulose acetate is nasallyadministered to rats.

FIG. 3 shows plasma SCT concentration versus time profile whencomparative powders (2 kinds) containing SCT are nasally administered torats.

FIG. 4 shows plasma SCT concentration versus time profile whencomparative solutions (2 kinds) containing SCT are nasally administeredto rats.

FIG. 5 shows plasma human insulin sodium salt (hereinafter referred toas INS) concentration versus time profile when a powder foradministration containing INS, NAC and EC, and a comparative solutioncontaining INS are each nasally administered to rats.

FIG. 6 shows plasma human parathyroid hormone 1-34 (hereinafter referredto as PTH) concentration versus time profile when a powder foradministration containing PTH, NAC and EC, and a comparative solutioncontaining PTH are each nasally administered to rats.

FIG. 7 shows plasma SCT concentration versus time profile when a powderfor administration containing SCT, NAC and EC, and a comparativesolution containing SCT are each nasally administered to dogs.

FIG. 8 shows plasma bovine insulin (hereinafter referred to as BINS)concentration versus time profile when a powder for administrationcontaining BINS, NAC and EC, and a comparative solution containing BINSare each nasally administered to dogs.

BEST MODE FOR CARRYING OUT THE INVENTION

In the non-water-absorbing and hardly water-soluble powder(s) to be usedfor the powdery preparation for nasal administration of the presentinvention, as a non-water-absorbing and hardly water-soluble substance,there may be mentioned a substance preferably having a water absorptionrate of 5 mm/min or less, and a solubility in water (25° C., hereinafterthe same) of 100 mg/L or less, more preferably a substance having awater absorption rate of 1 mm/min or less, and a solubility in water of50 mg/L or less, most preferably a substance having a water absorptionrate of 0.5 mm/min or less, and a solubility in water of 20 mg/L orless.

The water absorption rate means a value in which, according to themethod described in summary collection of 16th Symposium on ParticulatePreparations and Designs (1999), pp. 163 to 167, powder is filled in aglass tube having an inner diameter of 2.1 cm, while the glass tube ismaintained at a vertical state and a bottom end thereof is dipped inpure water, a distance from the bottom end of the glass tube to theupper end of water absorbed upward from the bottom end of the glass tubeis measured.

Also, the powdery preparation for nasal administration of the presentinvention is to be administered by spraying into nasal cavity using agas, so that it is in a powdery form as a whole, preferably containing asolvent such as water, etc. as little as possible.

Specific examples of the non-water-absorbing and hardly water-solublesubstances may include various kinds of materials such asnon-water-absorbing and hardly water-soluble cellulose derivatives (forexample, ethyl cellulose, cellulose acetate, nitro cellulose, cellulosetriacetate, cellulose acetate phthalate, hydroxypropyl-methyl cellulosephthalate, hydroxypropylmethyl cellulose acetate succinate,carboxymethylethyl cellulose, etc.), non-water-absorbing and hardlywater-soluble higher fatty acid and its ester or salt (hardened oil,hydrogenated soybean oil, carnauba wax, bleached beeswax, sucrose fattyacid ester, stearic acid, a salt of stearic acid, etc.),non-water-absorbing and hardly water-soluble biodegradable polymers(polylactic acid, polyglycolic acid, lactic acid-glycolic acidcopolymer, etc.), non-water-absorbing and hardly water-soluble syntheticpolymers (polyethylene terephthalate, polyethylene, polyvinyl chloride,etc.), non-water-absorbing and hardly water-soluble polyvalent metalsalt (calcium carbonate, barium sulfate, hydroxy-apatite, etc.),non-water-absorbing and hardly water-soluble metal oxides (talc, silicondioxide, titanium oxide, etc.), and the non-water-absorbing and hardlywater-soluble cellulose derivatives are preferably used, in particular,ethyl cellulose and/or cellulose acetate is/are preferably used, andfrom the view point of non-water-absorbing property, ethyl celluloseand/or cellulose acetate of a high substitution degree is/areparticularly preferred.

Here, the high substitution degree means that among the hydroxyl groupsof L-glucose constituting the cellulose molecule, hydrogen atoms of thehydroxyl groups which are not used for bonds between L-glucoses aresubstituted by a substituent(s) on an average of 70% or more, preferablyon an average of 80% or more, particularly preferably on an average of85% or more.

Also, as the non-water-absorbing and hardly water-soluble powder(s), itis preferred that mucus of the nasal mucous membrane, etc. are hardlyattached to the surface of the powder particles, so that the powderparticles having no cavity on their surface are preferred. Though anaverage diameter of the powder particles may vary depending on the kindsof the physiologically active substance, and the mucolytic agent- and/orthe nonionic surfactant to be contained in the powdery preparation fornasal administration, form of use, etc., it may be usually in the rangeof 5 to 200 μm, preferably in the range of 20 to 150 μm, more preferablyin the range of 30 to 120 μm, most preferably in the range of 40 to 100μm.

Though the non-water-absorbing and hardly water-soluble powder(s) may bethose which are commercially available powder product(s) as such, thenon-water-absorbing and hardly water-soluble solid substance may beprocessed or the commercially available powder product may be furtherprocessed to prepare a desired particle diameter and shape and theprocessed product is used.

Also, the non-water-absorbing and hardly water-soluble powder(s) may beone non-water-absorbing and hardly water-soluble powder, or a pluralnumber of non-water-absorbing and hardly water-soluble powders.

As a method of processing the non-water-absorbing and hardlywater-soluble substance, any conventional fine particle-formation methodcan be optionally used and there may be employed, for example, aphysically pulverizing method such as jet-mill pulverization, hummermill pulverization, rotary type ball mill pulverization, vibration ballmill pulverization, beads mill pulverization, shaker mill pulverization,rod mill pulverization, tube mill pulverization, etc.; a crystallizationmethod in which the non-water-absorbing and hardly water-solublesubstance is once dissolved in a solvent, then crystallized by changingtemperature, changing a composition of the solvents, etc., andrecovering by the method of centrifugation or filtration, etc.; a spraydrying method in which the non-water-absorbing and hardly water-solublesubstance is once dissolved in a solvent, and spraying the solution intoa drying room of a spray dryer using a spray nozzle to volatilize thesolvent in the sprayed solution within a short period of time, and thelike.

Also, the non-water-absorbing and hardly water-soluble powder(s) may besubjected to a treatment so that the particle diameter falls within apredetermined range by suppressing the fluctuation of the particlediameter by means of the method such as sieving, fractioning due tosedimentation by gravity, fractioning by centrifugation, fractioning byinertia force due to gas flow, etc.

One or two selected from the group consisting of a mucolytic agent(s)and a nonionic surfactant(s) mean either of (a) a mucolytic agent(s),(b) a nonionic surfactant(s) or (c) a mucolytic agent(s) and a nonionicsurfactant(s), and in either of (a) to (c), the mucolytic agent(s), andthe nonionic surfactant(s) may comprise only one component or maycomprise a plural number of components.

Though as the mucolytic agent- and/or the nonionic surfactant, anymaterial which can promote absorption of the physiologically activesubstance to the mucous membrane may be used, a material which has lessadverse effects on the nasal mucous membrane such as stimulatingproperty, etc., and which can markedly improve absorption from the nasalmucous membrane in a small amount may be preferably used. The mucolyticagent alone, or a combination of the mucolytic agent and the nonionicsurfactant are preferably used, and in view of stimulating property tothe nasal mucous membrane, the mucolytic agent is most preferably used.

As preferred examples of the mucolytic agents, there may be mentionedcysteine derivatives, and active SH group-containing alcohols. As thecysteine derivatives, there may be mentioned, for example, N-(C₂₋₅alkanoyl)cysteine such as N-acetylcysteine, etc., S-(C₁₋₄ alkyl)cysteinesuch as S-methylcysteine, S-ethylcysteine, etc., and S-(C₂₋₅carboxyalkyl)cysteine such as S-carboxymethylcysteine, etc.

Also, as the cysteine derivatives, cysteine-containing peptides areincluded, and there may be mentioned, for example, glutathiones whichare a kind of tripeptides. Examples of the glutathiones may include, inaddition to glutathione, glutathione esters such as a glutathione C₁₋₈alkyl ester (see U.S. Pat. No. 4,784,685), etc.

As the cysteine of these cysteine derivatives, DL-form, L-form andD-form are included, and in particular, L-cysteine is preferred.

As the active SH group-containing alcohol, there may be mentioned a C₃₋₆active SH group-containing alcohol, more specifically1,4-dithiothreitol.

As the nonionic surfactant, a nonionic surfactant which has lowprotein-denaturing ability and has low membrane solubilizing property ispreferred.

As such a nonionic surfactant may be mentioned a polyoxyethylene-C₁₀₋₁₄alkyl ether, a polyoxyethylene-(C₆₋₁₀ alkyl-phenyl) ether, a C₆₋₁₀alkyl-glucose ether and an N-(C₆₋₁₀ alkyl)carbamoyl-C₁₋₄ alkyl-glucoseether, etc.

As the polyoxyethylene-C₁₀₋₁₄ alkyl ether and the polyoxyethylene-(C₆₋₁₀alkyl-phenyl) ether, those having a polyoxyethylene portion in the rangeof 65 to 90% by weight based on the whole molecule are preferred, andthere may be specifically mentioned polyoxyethylene-lauryl ether havingan average molecular weight of 560 to 1300 [for example, BL-9 availablefrom Nikkol: polyoxyethylene(9) lauryl ether; BL-25: polyoxyethylene(25)lauryl ether]; polyoxy-ethylene-octylphenyl ether having an averagemolecular weight of 600 to 800, particularlypolyoxyethylene-tert-octylphenyl ether having an average molecularweight of 600 to 800 [for example, Triton X-100 available from Nacalai:polyoxyethylene (9-10) p-tert-octylphenyl ether, Triton X-102:polyoxyethylene (12-13) p-tert-octylphenyl ether];polyoxyethylene-nonylphenyl ether having an average molecular weight of600 to 700, particularly polyoxyethylene-n-nonylphenyl ether having anaverage molecular weight of 600 to 700 [for example, NP-10 availablefrom Nikkol: polyoxyethylene (10) p-n-nonylphenyl ether].

As the C₆₋₁₀ alkyl-glucose ether and N-(C₆₋₁₀ alkyl)-carbamoyl-C₁₋₄alkyl-glucose ether, those having a glucose portion in the range of 50to 65% by weight based on the whole molecule is preferred, and there maybe specifically mentioned 1-O-octyl-β-D-glucopyranoside, particularly1-O-n-octyl-β-D-glucopyranoside;6-O-(N-heptylcarbamoyl)methyl-α-D-glucopyranoside, particularly6-O-(N-n-heptylcarbamoyl)methyl-α-D-glucopyranoside.

Moreover, as the nonionic surfactant, a nonionic surfactant whoseconcentration in an aqueous solution at which 50% of red blood cells arehemolysed is 1% by weight or more, particularly 5% by weight or more, ispreferred since it causes less adverse effects on the nasal mucousmembrane.

Here, the concentration of the nonionic surfactant in an aqueoussolution at which 50% of red blood cells are hemolysed can be estimatedby the following method. Red blood cells are added in a ratio of 0.2% byweight to physiological salines containing the nonionic surfactant whichhad been adjusted to various concentrations, the mixtures are allowed tostand at 37° C. for 10 minutes, and the absorbance (540 nm) ofhemoglobin in the supernatant is measured. On the other hand, when redblood cells are added to purified water with the same ratio and arecompletely hemolysed, the absorbance is considered to be 100%. Hemolysisratios of the red blood cells at the respective concentrations of thenonionic surfactant are calculated, whereby the concentration of thenonionic surfactant at which the hemolysis ratio becomes 50% isestimated by an interpolation method.

As the physiologically active substance, it is not particularly limitedso long as it is a medicine having less stimulation to nasal mucousmembrane, but a physiologically active substance which shows medicinaleffect with a small dose is preferred since a large amount of medicinecannot be administered by nasal administration.

Also, when the powdery preparation for nasal administration of thepresent invention is applied to a physiologically active substance whichcan be hardly absorbed by nasal route, improvement in nasal absorptionof the physiologically active substance becomes remarkable, so that ahydrophilic hardly-absorbable substance is preferably used as thephysiologically active substance.

Incidentally, the term hardly-absorbable means that when an aqueoussolution of a physiologically active substance is nasally administeredto human by spraying, 5% or less of the sprayed amount is absorbed.

As such a physiologically active substance may be mentioned those usedas antibiotics, blood-forming agents, infectious diseases treatingagents, anti-dementia, antiviral agents, anti-tumor agent, antipyreticagents, analgesic, anti-inflammatory, antiulcer, antiallergic agent,antipsychotic medicine, cardiotonic agent, cardiac dysrhythmia treatingagent, vasodilators, hypotensive agent, diabetes treating agent,anticoagulant, cholesterol lowering agent, osteoporosis treating agent,hormone agent, vaccine, etc.

As these substances, in addition to the low molecular weightphysiologically active substance, peptidic physiologically activesubstance, polysaccharide physiologically active substance, etc. areincluded, and the powdery preparation for nasal administration of thepresent invention shows marked effects when it is applied to thepeptidic physiologically active substance and/or polysaccharidephysiologically active substance, and it is particularly preferablyapplied to the peptidic physiologically active substance.

As the peptidic physiologically active substances, there may bementioned an antagonist, agonist or soluble receptors thereof andderivatives thereof, and with regard to a substance having sugar chain,those which have a different structure in chain are also included. Ifnecessary, these substances may be modified by a synthetic polymer suchas polyethylene glycol, etc., or a natural polymer such as hyaluronicacid, etc., or else, may be modified by an optional sugar such asgalactose, mannose, etc., or may be modified by a sugar chain ornon-peptidic compound. Also, they may be a substance which provides alipid-soluble property to the peptidic physiologically active substance,such as phospholipids, fatty acids, etc. These peptidic physiologicallyactive substances have a molecular weight of 200 to 200000, preferablyhave a molecular weight of 200 to 50000, more preferably have amolecular weight of 200 to 25000, and most preferably have a molecularweight of 200 to 10000.

Preferred peptidic physiologically active substances may includecytokine, peptide hormone, growth factor, a factor which acts on cardiacvessel system, a factor which acts on central and peripheral nervesystems, etc., and specific examples are as mentioned below.

As the cytokine, there may be mentioned interferons (for example,interferon-α, -β, -γ), interleukins (for example, interleukin-1 to 11),tumor necrosis factor (for example, TNF-α, -β), leukemia inhibitoryfactor (LIF), blood-forming factor [for example, erythropoietin,thrombopoietin, granulocyte colony stimulating factor (G-CSF),granulocyte-macrophage colony stimulating factor (GM-CSF), macrophagecolony stimulating factor (M-CSF)], etc.

As the peptide hormone, there may be mentioned insulin, growth hormone,gonadotropic hormone, melanocyto-stimulating hormone, luteotropichormone, leuteinizing hormone, leuteinizing hormone-releasing hormone(LH-RH) and its derivatives (goserelin, buserelin, leuprorelin),adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH),thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH)and its derivatives (taltirelin), calcitonin, etc.

As the growth factor, there may be mentioned nerve growth factors (forexample, NGF, NGF-2/NT-3), epidermal growth factor (EGF), fibroblastgrowth factor (FGF), insulin-like growth factor (IGF), transforminggrowth factor (TGF), platelet-derived growth factor (PDGF), hepatocytesgrowth factor (HGF), etc.

As the factor which acts on cardiac vessel system, there may bementioned endothelin, endothelin inhibitor, endothelin antagonist,endothelin formation enzyme inhibitor, desmopressin, renin, angiotensinI to III, atrial natriumuretic peptide (ANP), etc.

As the factor which acts on central and peripheral nerve systems, theremay be mentioned enkephalin, endorphin, dynorphin, neoendorphin, etc.

In these peptidic physiologically active substances, a soluble receptorof the polypeptide is included in the concept. In these peptidicphysiologically active substance, those which are chemically modified bya polymer such as polyethylene glycol, or by a natural polymer such aschondroitin, polysaccharides, or by a non-peptidic substance may berespectively included. The non-peptidic substance herein mentioned maybe a ligand to a receptor, or an antigen to an antibody. Moreover, theabove-mentioned peptidic physiologically active substance may includethose in which a plural number of peptides are bound by a chemicalmethod or a genetic recombinant technique.

As the physiologically active polysaccharide substance, there may bementioned a low molecular weight heparin, a heparin-like substance, etc.

Also, in the powdery preparation for nasal administration of the presentinvention, the physiologically active substance can be taken into a bodyfrom a blood vessel system under the mucous membrane of the nasal cavityimmediately after administration, and a time interval from theadministration to the generation of the medicinal effects is short.Therefore, it can also be suitably employed for a physiologically activesubstance with which a short onset time (a time interval between theadministration of a medicine and the generation of the medicinaleffects) produces therapeutic advantages.

Thus, the powdery preparation for nasal administration of the presentinvention can be suitably applied to a physiologically active substance,for example, narcotic analgesic (for example, alkaloid type narcotic),migraine treating agent [for example, 5-hydroxytryptamine (HT) 1receptor agonist, neurokinin (NK) 1 receptor antagonist, iGluR5 receptorantagonist, β adrenergic blocking agent], preventive for travel sickness[for example, central anti-cholinergic agent, anti-histaminic agent,5-hydroxytryptamine (HT) 1 receptor agonist], antiemetic [for example,neurokinin (NK) 1 receptor antagonist, 5-hydroxytryptamine (HT) 3receptor antagonist], sexual function improving agent [for example,phosphodiesterase (PDE) 5 inhibitor, α-melanin cell stimulating hormone(MSH) analogue, dopamine D2 receptor agonist, non-steroidal androgenreceptor modulator], diabetes treating agent (for example, insulin),first aid medicine at the time of low blood sugar (for example,glucagon), etc.

Though a formulation ratio of the powdery preparation for nasaladministration of the present invention may vary depending on variousfactors such as a kind of the physiologically active substance, kinds ofthe mucolytic agent- and/or the nonionic surfactant, used form thereof,etc., the physiologically active substance may be used in an amount of0.1 to 80% by weight based on the whole preparation, thenon-water-absorbing and hardly water-soluble powder(s) may be used inthe amount of 15 to 99.4% by weight based on the same, and the mucolyticagent- and/or the nonionic surfactant may be used in the amount of 0.5to 5% by weight based on the same.

A (spraying/inhalation) dose of the powdery preparation for nasaladministration of the present invention is generally 3 to 50 mg/ time,preferably 5 to 20 mg/each time. Even in such a small amount of(spraying/inhalation) dose, the powdery preparation for nasaladministration of the present invention can give an excellent nasalabsorption promoting effect by using a small amount of thenon-water-absorbing and hardly water-soluble powder(s), and themucolytic agent- and/or the nonionic surfactant. Thus, a physiologicallyactive substance which is required to be absorbed in a living body at arelatively large dose (1 mg/person/time or so) for generating aphysiological activity can be nasally absorbed.

Also, the non-water-absorbing and hardly water-soluble powder(s) does/donot itself show any physiological activity at the nasal mucous membrane,so that when a physiologically active substance which shows sufficientphysiological activity with a small (spraying/inhalation) dose is to benasally administered, an amount of the non-water-absorbing and hardlywater-soluble powder(s) may be intentionally increased to controlfluctuation of a dose of the physiologically active substance to beadministered per one spraying/inhalation.

The physiologically active substance, and the mucolytic agent- and/orthe nonionic surfactant to be contained in the powdery preparation fornasal administration of the present invention can be mixed in a powderstate with the non-water-absorbing and hardly water-soluble powder(s) togive the powdery preparation for nasal administration of the presentinvention, and the preparation can be used as such. However, in thiscase, it is preferred to regulate a density and particle diameter of thepowder particles in order to prevent the respective components fromseparation at the time of administration into nasal cavity byspraying/inhalation.

For example, it is preferred that densities calculated from the outershape of the physiologically active substance, and the mucolytic agent-and/or the nonionic surfactant are in the range of 0.7 to 1.5-fold tothe density calculated from the outer shape of the non-water-absorbingand hardly water-soluble powder(s), preferably in the range of 0.8 to1.3-fold, and the particle diameters of the powder of thephysiologically active substance, and the mucolytic agent- and/or thenonionic surfactant are in the range of 0.3 to 1.2-fold to the particlediameter of the non-water-absorbing and hardly water-soluble powder(s),preferably in the range of 0.4 to 1.1-fold.

Preparation of powder and designing of the particle diameter of thephysiologically active substance, and the mucolytic agent- and/or thenonionic surfactant can be also carried out by using the means usefulfor forming the non-water-absorbing and hardly water-soluble powder(s).When the physiologically active substance is a peptidic substance,preparation of powder can be carried out with maintaining physiologicalactivity thereof by lyophilizing an aqueous mixed solution of thepeptidic physiologically active substance and polyethylene glycol, andadding an organic solvent which does not dissolve the polypeptide butdissolves polyethylene glycol to the resulting solid material (JapaneseUnexamined Patent Publication No. Hei. 11-302156), or by adding anorganic solvent which does not dissolve a peptide and is water-miscibleto a frozen product of an aqueous mixed solution containing a peptidicphysiologically active substance and a phase-separation inducing agent(WO 02/30449), and recovering powder of the peptidic physiologicallyactive substance from the formed suspension.

Also, the physiologically active substance and/or the mucolytic agent-and/or the nonionic surfactant can be used by fixing on the surface ofthe non-water-absorbing and hardly water-soluble powder(s) to prepare apowdery preparation for nasal administration of the present invention,and can be used in this form.

For example, the physiologically active substance and/or the mucolyticagent- and/or the nonionic surfactant is/are dissolved in an aqueoussolvent (for example, water, aqueous ethanol, aqueous acetone, aqueousmethanol, aqueous acetonitrile), the solution is added to thenon-water-absorbing and hardly water-soluble powder(s), the mixture isdried by the method such as drying under reduced pressure, drying atnormal temperature, lyophilization, etc., and if necessary, theresulting product is sieved, to fix the physiologically active substanceand/or the mucolytic agent- and/or the nonionic surfactant on thesurface of the non-water-absorbing and hardly water-soluble powder(s).

Alternatively, an aqueous solvent (for example, water, aqueous ethanol,aqueous acetone, aqueous methanol, aqueous acetonitrile) is added to amixture of the powder of a non-water-absorbing and hardly water-solublesubstance, the physiologically active substance and/or the mucolyticagent- and/or the nonionic surfactant. The resulting mixture is kneaded,dried, again pulverized and sieved to have a desired particle diameter,whereby the physiologically active substance and/or the mucolytic agent-and/or the nonionic surfactant is/are fixed on the non-water-absorbingand hardly water-soluble powder(s) to prepare the powdery preparationfor nasal administration of the present invention.

Incidentally, the powdery preparation for nasal administration of thepresent invention is administered in a dry state, and no solvent isadded to the preparation. However, when the other powder solidcomponents do not exert any adverse effects on the nasal mucousmembrane, and do not inhibit nasal absorption, other additionalcomponents may be added in a small amount to increase the total amountof the preparation so that an administration (spraying/inhalation) doseof the physiologically active substance per one time becomes constantand the stability of the physiologically active substance is improved.

As such a component to be added in a small amount may be mentioned, forexample, a lubricant [talc, stearic acid and its salt (sodium salt,calcium salt), Carplex, etc.], a binder (starch, dextrin, etc.), a pHadjusting agent (citric acid, glycine, etc.), a preserver (ascorbicacid, etc.), an antiseptic agent (paraoxybenzoates, benzalkoniumchloride, phenol, chlorobutanol, etc.), odor masking agent (menthol,citrus flavoring, etc.).

The powdery preparation for nasal administration of the presentinvention can be administered into nasal cavity by spraying, and apredetermined amount of the powdery preparation for nasal administrationcan be sprayed into the nasal cavity with air or a gas (air, nitrogengas, argon gas, carbon dioxide gas, substitute flon gas, etc.) whichdoes not cause any adverse effect to human body.

As a method of spraying, any conventionally used devices for nasaladministration can be used, and for example, there may be considered amethod in which the powdery preparation for nasal administration of thepresent invention is filled in a device for pressure administration witha predetermined dose spraying system, and is sprayed into nasal cavitywith each predetermined dose, a method in which the powdery preparationfor nasal administration of the present invention is filled in acapsule, etc. in a predetermined amount, and when necessity arises, thecapsule, etc. is mounted as such on the device for pressureadministration and is made by perforation, etc. in a state wherein thepowdery preparation for nasal administration can be sprayed, and thepowdery preparation is sprayed with air or a gas which does not exertany adverse effects on the human body into nasal cavity, and the like.

Further, a spraying speed of air or a gas which does not exert anyadverse effects on the human body at the time of spraying is preferablycontrolled so that almost all the constitutional components of thepowdery preparation for nasal administration reaches mucous membranes ofconcha nasalis superior, concha nasalis media, concha nasalis inferiorwhich have the most efficient absorption ratio among the mucousmembranes of the nasal cavity, and in addition to the spraying speed ofthe gas, the powdery preparation for nasal administration is sprayedsynchronized with the inhalation of air through the nose of the patientto be nasally administered to give more efficient delivery thereof tothe absorption site.

Moreover, the powdery preparation for nasal administration of thepresent invention can be nasally absorbed only by inhalation withoutspraying it into the nasal cavity. The powdery preparation for nasaladministration of the present invention is filled in a blister pack,etc. with a predetermined dose, and when necessity arises, it is mountedas such on a inhalation device, and is converted to a state that thepowdery preparation for nasal administration can be taken out bypressure, etc., and the preparation is subjected to inhalation wherebythe powdery preparation for nasal administration can reach the nasalcavity.

Concomitantly, the powdery preparation for nasal administration of thepresent invention can be used for administration through lung,administration through pharynx mucous membrane, etc., or may beadministered to a patient by using a conventionally used administrationdevice (spraying/inhalation device for administration through lung,spraying device for administration through pharynx mucous membrane,etc.) according to the administration method.

EXAMPLE

Next, the present invention is explained more concretely by referring toExamples, but the scope of the present invention is not limited bythese.

Example 1

1.0 mg of salmon calcitonin (molecular weight: 3431.9, available fromBACHEM Co., average particle diameter: 36.6 μm, hereinafter referred toas SCT), 1.5 mg of N-acetyl-L-cysteine (available from Fluka, averageparticle diameter: 45.8 μm, hereinafter referred to as NAC) and 27.5 mgof ethyl cellulose (available from Dow Chemical, Ethocel #10, averageparticle diameter: 81.4 μm, ethylation degree: 87 to 90%, hereinafterreferred to as EC) were mixed well to give a powder for administration.

Example 2

1.0 mg of SCT, 1.5 mg of NAC and 27.5 mg of cellulose acetate (availablefrom Katayama Chemical Industries Co., Ltd., average particle diameter:88.0 μm, acetylation degree: 53 to 56%, hereinafter the same) were mixedwell to give a powder for administration.

Example 3

In 0.3 ml of 30% aqueous ethanol was dissolved 10 mg of human insulinsodium salt (molecular weight: 5749.5, available from Sigma, hereinafterreferred to as INS), the resulting solution was added to 90 mg of EC,and the resulting mixture was dried under reduced pressure at roomtemperature overnight to give a mixed powder of INS and EC. 10 mg of thethus-obtained mixed powder of INS and EC, 1.5 mg of NAC and 18.5 mg ofEC were mixed well to give a powder for administration.

Example 4

In 0.3 ml of 30% aqueous ethanol was dissolved 5 mg of human parathyroidhormone 1-34 (molecular weight: 4117.8, available from BACHEM Co.,hereinafter referred to as PTH), the resulting solution was added to 45mg of EC, and the resulting mixture was dried under reduced pressure atroom temperature overnight to give a mixed powder of PTH and EC. 10 mgof the thus-obtained mixed powder of PTH and EC, 1.5 mg of NAC and 18.5mg of EC were mixed well to give a powder for administration.

Example 5

In 0.3 ml of 30% aqueous ethanol was dissolved 10 mg of SCT, theresulting solution was added to 90 mg of EC, and the resulting mixturewas dried under reduced pressure at room temperature overnight to give amixed powder of SCT and EC. 30 mg of the thus-obtained mixed powder ofSCT and EC, 1.5 mg of NAC and 68.5 mg of EC were mixed well to give apowder for administration.

Example 6

In 60 g of 20% aqueous ethanol containing 0.1N-HCl was dissolved 3 g ofbovine insulin (molecular weight: 5800, available from Sigma,hereinafter referred to as BINS), the resulting solution was added to 97g of EC, and the resulting mixture was stirred and mixed by a smallsized high speed mixer and dried at 50° C. for 4 hours to give a mixedpowder of BINS and EC. 1.5 g of NAC was similarly dissolved in 60 g of20% aqueous ethanol, the resulting solution was added to 98.5 g of EC,and the resulting mixture was stirred and mixed by a small sized highspeed mixer and dried at 50° C. for 4 hours to give a mixed powder ofNAC and EC. The thus-obtained mixed powder of BINS and EC and the mixedpowder of NAC and EC were mixed well in equal amounts to give a powderfor administration.

Preparation Example 1

Disposable tip (manufactured by Nichiryo Co., Ltd., for 200 μl),three-way stop-cock (manufactured by Terumo Corporation) and a 1 mlsyringe (manufactured by Terumo Corporation) were connected in thisorder to prepare a device for nasal administration of powder.

The top portion of the disposable tip of this device was filled withadministration powder, and air was fed by the syringe, whereby theadministration powder was to be sprayed to nasal cavity.

Comparative Examples 1 to 2

1.0 mg of SCT, 1.5 mg of NAC and 27.5 mg of the component shown in thenext Table 1 were mixed well to give comparative powders.

TABLE 1 Comparative example No. Components 1 Lactose (available fromWako Pure Chemical Industries, Ltd., sieved so that the powder consistsof particles of 150 μm or less in diameter) 2 Crystalline cellulose(available from Asahi Kasei Corporation, AVICEL PH-101, sieved so thatthe powder consists of particles of 150 μm or less in diameter, averageparticle diameter: 23.2 μm, hereinafter the same)

Comparative Example 3

In 0.05 ml of a physiological saline for injection (available fromOtsuka Pharmaceutical Co., Ltd., hereinafter the same) was dissolved 1.0mg of SCT to give a comparative solution.

Comparative Example 4

In 0.05 ml of a physiological saline for injection were dissolved 1.0 mgof SCT and 2.5 mg of NAC to give a comparative solution.

Comparative Example 5

In 0.05 ml of a physiological saline for injection was dissolved 1.0 mgof INS to give a comparative solution.

Comparative Example 6

In 0.05 ml of a physiological saline for injection was dissolved 1.0 mgof PTH to give a comparative solution.

Comparative Example 7

In 1.0 ml of a physiological saline for injection was dissolved 3.0 mgof SCT to give a comparative solution.

Comparative Example 8

In 1.0 ml of a physiological saline for injection was dissolved 3.0 mgof BINS to give a comparative solution.

Experimental Example 1

-   (1) Wistar male rats (9 to 11-weeks old, body weight: 190 to 260 g,    available from Nippon SLC) were accustomed to the conditions of 12    hours illumination at room temperature 23 ±2° C., supplied freely    with water and food for 1 week. Thereafter, rats were fasted for    about 20 hours before the experiment, and after anesthesia with 50    mg/kg of pentobarbital (available from Nacalai), an operation for    nasal administration was applied thereto according to the method    described in International Journal of Pharmaceutics, vol. 7, pp. 317    to 325 (1981).-   (2) With regard to the operated rats, a powder for administration    prepared in Example 1 or 2 was administered by spraying to one of    the nasal cavities of the rats of the administration group by using    a device for nasal administration of powder assembled in Preparation    example 1 so that a dose of SCT became 0.1 mg/rat.

On the other hand, to the comparative group, a comparative powderprepared in Comparative example 1 or 2 was administered by spraying toone of the nasal cavities of the rats so that a dose of SCT became 0.1mg/rat. Alternatively, a comparative solution prepared in Comparativeexample 3 or 4 was administered to one of the nasal cavities of the ratby using micropipette so that a dose of SCT became 0.1 mg/rat.

-   (3) After 5, 10, 20, 30, 45, 60, 90 and 120 minutes from the    administration by spraying, blood was sampled each in an amount of    0.1 ml from the jugular vein with a syringe (manufactured by Terumo    Corporation, 25 G) treated by heparin (available from Mochida    Pharmaceutical Co., Ltd.), and was centrifuged (12000 rpm, 3    minutes) to obtain plasma. SCT concentration in plasma was measured    by using an enzyme immunoassay kit for measuring SCT (manufactured    by Peninsula Laboratories).

The results of the measurement of an SCT concentration in plasma withregard to the powders for administration prepared in Examples 1 and 2are shown in FIG. 1 and FIG. 2, respectively, and the results of themeasurement of SCT concentration in plasma with regard to thecomparative powders in Comparative examples 1 and 2 and the comparativesolutions of Comparative examples 3 and 4 are shown in FIG. 3 and FIG.4, respectively.

In these figures, the point indicates an average value of 3 to 5samples, and the bar indicates a standard deviation.

Also, in these figures, AUC (Area Under Curve) was calculated accordingto the conventional manner, and BA (Bioavailability) by nasaladministration was calculated by comparing with AUC calculated from theseparate measurement results of the SCT concentration in plasma by anintravenous administration of SCT at a dose of 0.1 mg/rat (using 500μg/ml of a physiological saline solution for injection of SCT). Theresults are shown in the following Table 2.

TABLE 2 BA (%) until 2 hours after Test materials administration Powderfor administration 29.7% prepared in Example 1 Powder for administration40.7% prepared in Example 2 Comparative powder prepared 15.3% inComparative example 1 Comparative powder 10.5% prepared in Comparativeexample 2 Comparative solution  7.4% prepared in Comparative example 3Comparative solution 15.7% prepared in Comparative example 4 Solution(intravenous  100% administration)

Experimental Example 2

-   (1) With regard to rats obtained in Experimental example 1(1), the    powder for administration prepared in Example 3 was administered by    spraying to one of the nasal cavities of the rats of the    administration group by using a device for nasal administration of    powder assembled in Preparation example 1 so that a dose of INS    became 0.1 mg/rat.

On the other hand, to the comparative group, the comparative solutionprepared in Comparative example 5 was administered to one of the nasalcavities of the rat by using micropipette so that a dose of INS became0.1 mg/rat.

-   (2) After 5, 10, 20, 30, 45, 60, 90 and 120 minutes from the spray    administration, blood was sampled each in an amount of 0.1 ml from    the jugular vein with a syringe (manufactured by Terumo Corporation,    25 G) treated by heparin (available from Mochida Pharmaceutical Co.,    Ltd.), and was centrifuged (12000 rpm, 3 minutes) to obtain plasma.    Total insulin (INS and rat insulin) concentration in plasma was    measured by using an enzyme immunoassay kit for measuring insulin    (manufactured by Wako Pure Chemical Industries, Ltd.). Incidentally,    INS concentrations in plasma at the respective measurement points    were shown as a value by subtracting a rat insulin concentration in    blood before administration from the respective measurement values.

The results of the measurement of an INS concentration in plasma withregard to the powder for administration prepared in Example 3 and thecomparative solution prepared in Comparative example 5 are shown in FIG.5.

In these figures, the point indicates an average value of 5 to 7samples, and the bar indicates a standard deviation.

Also, in these figures, AUC (Area Under Curve) was calculated accordingto the conventional manner, and BA (Bioavailability) by nasaladministration was calculated by comparing with AUC calculated from theseparate measurement results of the INS concentration in plasma by anintravenous injection of INS at a dose of 0.1 mg/rat (using 200 μg/ml ofa physiological saline solution for injection of INS). The results areshown in the following Table 3.

TABLE 3 BA (%) until 2 hours Test materials after administration Powderfor administration 23.4% prepared in Example 3 Comparative solution10.5% prepared in Comparative example 5 Solution (intravenous  100%administration)

Experimental Example 3

-   (1) With regard to rats obtained in Experimental example 1(1), the    powder for administration prepared in Example 4 was administered by    spraying to one of the nasal cavities of the rats of the    administration group by using a device for nasal administration of    powder assembled in Preparation example 1 so that a dose of PTH    became 0.1 mg/rat.

On the other hand, to the comparative group, the comparative solutionprepared in Comparative example 6 was administered to one of the nasalcavities of the rat by using micropipette so that a dose of PTH became0.1 mg/rat.

-   (2) After 5, 10, 20, 30, 45, 60, 90 and 120 minutes from the spray    administration, blood was sampled each in an amount of 0.1 ml from    the jugular vein with a syringe (manufactured by Terumo Corporation,    25 G) treated by heparin (available from Mochida Pharmaceutical Co.,    Ltd.), and was centrifuged (12000 rpm, 3 minutes) to obtain plasma.    PTH concentration in plasma was measured by using an enzyme    immunoassay kit for measuring PTH (manufactured by Peninsula    Laboratories).

The results of the measurement of a PTH concentration in plasma withregard to the powder for administration prepared in Example 4 and thecomparative solution prepared in Comparative example 6 are shown in FIG.6.

In these figures, the point indicates an average value of 7 samples, andthe bar indicates a standard deviation.

Also, in these figures, AUC (Area Under Curve) was calculated accordingto the conventional manner, and BA (Bioavailability) by nasaladministration was calculated by comparing with AUC calculated from theseparate measurement results of the PTH concentration in plasma byintravenous injection of PTH at a dose of 0.01 mg/rat (using 200 μg/mlof a physiological saline solution for injection of PTH). The resultsare shown in the following Table 4.

TABLE 4 BA (%) until 2 hours after Test materials administration Powderfor administration 28.2% prepared in Example 4 Comparative solution 8.5% prepared in Comparative example 6 Solution (intravenous  100%administration)

Experimental Example 4

-   (1) Male beagle dogs (2 year-old, body weight of 12.2 to 15.1 kg,    available from Kitayama Labes Co., Ltd.) were fasted for about 20    hours before the experiment, and after anesthesia with 40 mg/kg of    pentobarbital (available from Nacalai), the powder for    administration prepared in Example 5 was administered by spraying to    one of the nasal cavities of the dogs of the administration group by    using a device for nasal administration of powder (Bi-Dose Nasal    Powder device, manufactured by Pfeiffer Co.) so that a dose of SCT    became 0.3 mg/dog.

On the other hand, to the comparative group, the comparative solutionprepared in Comparative example 7 was administered to one of the nasalcavities of the dogs by using micropipette so that a dose of SCT became0.3 mg/dog.

-   (3) After 5, 10, 20, 30, 45, 60, 90 and 120 minutes from the spray    administration, blood was sampled each in an amount of 1 ml from the    foreleg vein with a syringe (manufactured by Terumo Corporation,    25 G) treated by heparin (available from Mochida Pharmaceutical Co.,    Ltd.), and was centrifuged (12000 rpm, 3 minutes) to obtain plasma.    SCT concentration in plasma was measured by using an enzyme    immunoassay kit for measuring SCT (manufactured by Peninsula    Laboratories).

The results of the measurement of an SCT concentration in plasma withregard to the powder for administration prepared in Example 5 and thecomparative solution prepared in Comparative example 7 are shown in FIG.7.

In these figures, the point indicates an average value of 5 samples, andthe bar indicates a standard deviation.

Also, in these figures, AUC (Area Under Curve) was calculated accordingto the conventional manner, and BA (Bioavailability) by nasaladministration was calculated by comparing with AUC calculated from themeasurement results of the SCT concentration in plasma by intravenousinjection of SCT to dogs at a dose of 5 mg/dog (using 2.5 mg/ml of aphysiological saline solution for injection of SCT). The results areshown in the following Table 5.

TABLE 5 BA (%) until 2 hours Test materials after administration Powderfor administration 23.1% prepared in Example 5 Comparative solution 8.4% prepared in Comparative example 7 Solution (intravenous  100%administration)

Experimental Example 5

-   (1) Male beagle dogs (3 year-old, body weight of 11.3 to 16.2 kg,    available from Kitayama Labes Co., Ltd.) were fasted for about 20    hours before the experiment, and after anesthesia with 40 mg/kg of    pentobarbital (available from Nacalai), the powder for    administration prepared in Example 6 was administered by spraying to    one of the nasal cavities of the dogs of the administration group by    using a device for nasal administration of powder (Bi-Dose Nasal    Powder device, manufactured by Pfeiffer Co.) so that a dose of BINS    became 0.3 mg/dog.

On the other hand, to the comparative group, the comparative solutionprepared in Comparative example 8 was administered to one of the nasalcavities of the dogs by using micropipette so that a dose of BINS became0.3 mg/dog.

-   (2) Before spray administration and after 5, 10, 15, 20, 30, 45, 60,    90 and 120 minutes from the administration, blood was sampled each    in an amount of 1 ml from the foreleg vein with-a syringe    (manufactured by Terumo Corporation, 25 G) treated by heparin    (available from Mochida Pharmaceutical Co., Ltd.), and was    centrifuged (12000 rpm, 3 minutes) to obtain plasma. Total insulin    (BINS and dog insulin) concentration in plasma was measured by using    an enzyme immunoassay kit for measuring insulin (manufactured by    Wako Pure Chemical Industries, Ltd.). Incidentally, BINS    concentrations in plasma at the respective measurement points were    shown as a value by subtracting a dog insulin concentration in blood    before administration from the respective measurement values.

The results of the measurement of a BINS concentration in plasma withregard to the powder for administration prepared in Example 6 and thecomparative solution prepared in Comparative example 8 are shown in FIG.8.

In these figures, the point indicates an average value of 3 or 4samples, and the bar indicates a standard deviation.

Also, in these figures, AUC (Area Under Curve) was calculated accordingto the conventional manner, and BA (Bioavailability) by nasaladministration was calculated by comparing with AUC calculated from themeasurement results of the BINS concentration in plasma by intravenousinjection of BINS at a dose of 0.3 mg/dog (using 0.3 mg/ml of aphysiological saline solution for injection of BINS). The results areshown in the following Table 6.

TABLE 6 BA (%) until 2 hours Test materials after administration Powderfor administration  6.0% prepared in Example 6 Comparative solution 1.3% prepared in Comparative example 8 Solution (intravenous  100%administration)

Reference Example

According to the method described in summary collection of 16thSymposium on Particulate Preparations and Designs (1999), pp. 163 to167, water absorption properties of EC, cellulose acetate andcrystalline cellulose were investigated by the following method.

Namely, each 10 g of EC, cellulose acetate and crystalline cellulose wascharged in a glass tube (inner diameter: 2.1 cm, length: 7.8 cm) fordisintegration test, the bottom end of which had been capped with afilter paper. The tube was tapped with the other side down and wasallowed to stand vertically in a vessel filled with pure water with adepth of 10 mm at room temperature for 1 minute.

The glass tube was taken out after 1 minute, and a distance from thebottom end thereof to the upper end portion of upward water absorptionin the content in the glass tube was measured, and was estimated to be adistance of water absorption per 1 minute, which is an index of waterabsorption property. The results are shown in the following Table 7.

TABLE 7 Distance of water Name of component absorption EC 0.0 mm/minCellulose acetate 0.7 mm/min Crystalline cellulose 38.0 mm/min 

Utilizability in Industry

When the powdery preparation for nasal administration of the presentinvention is sprayed/inhaled into nasal cavity, due to the presence ofthe non-water-absorbing and hardly water-soluble powder(s), thephysiologically active substance and the mucolytic agent- and/or thenonionic surfactant are attached to mucous membrane of the nasal cavityand retained, and yet the non-water-absorbing and hardly water-solublepowder(s) does/do not absorb mucus of the nasal mucous membrane, so thatthe physiologically active substance and the mucolytic agent and/or thenonionic surfactant are dissolved in a minute amount of the mucus,whereby the physiologically active substance and the mucolytic agent-and/or the nonionic surfactant causes locally high concentrationsolution. In such a state, by utilizing concentration gradient of thephysiologically active substance, and according to the action of themucolytic agent- and/or the nonionic surfactant dissolved with a highconcentration, absorption property itself of the nasal mucous membraneis locally improved and the physiologically active substance can reachfrom the nasal mucous membrane the blood vessel system existing underthe membrane with good efficiency, whereby nasal absorption of thephysiologically active substance can be promoted.

Also, the non-water-absorbing and hardly water-soluble powder(s) does/donot itself absorb a medicine dissolved in the nasal cavity, so that autilization rate of the medicine is not lowered.

Moreover, the powdery preparation for nasal administration of thepresent invention acts on the nasal mucous membrane locally andscatteringly, so that it does not act on the whole nasal mucous membraneas in the liquid preparation for nasal administration, whereby it causesless adverse effects on the nasal mucous membrane.

1. A powdery preparation for nasal administration which comprises a physiologically active substance, a non-water-absorbing and hardly water-soluble cellulose derivative powder(s) and a mucolytic cysteine derivative(s) or a combination of a mucolytic cysteine derivative(s) and a nonionic surfactant(s).
 2. The powdery preparation for nasal administration according to claim 1, wherein the non-water-absorbing and hardly water-soluble cellulose derivative is a substance having a water absorption rate of 5 mm/mm or less and solubility in water at 25° C. of 100 mg/L or less.
 3. The powdery preparation for nasal administration according to claim 2, wherein the non-water-absorbing and hardly water-soluble cellulose derivative is a substance having a water absorption rate of 1 mm/mm or less and solubility in water at 25° C. of 50 mg/L or less.
 4. The powdery preparation for nasal administration according to claim 1, wherein the preparation contains the physiologically active substance, and the non-water-absorbing and hardly water-soluble cellulose derivative powder(s), together with a mucolytic cysteine derivative(s).
 5. The powdery preparation for nasal administration according to claim 1, wherein the physiologically active substance is a hydrophilic hardly-absorbable substance.
 6. The powdery preparation for nasal administration according to claim 1, wherein the physiologically active substance is a physiologically active substance with which a short on-set time produces therapeutic advantages.
 7. The powdery preparation for nasal administration according to claim 1, wherein an average particle diameter of the non-water-absorbing and hardly water-soluble soluble cellulose derivative powder(s) is in the range of 5 to 200 μm, and the densities and particle diameters of the powder of the physiologically active substance and powder(s) of the mucolytic cysteine derivative(s) or the combination of the mucolytic cysteine derivative(s) and the nonionic surfactant(s) are so controlled so that the dissipation state at the time of spraying/inhalation will be the same as those of the non-water-absorbing and hardly water-soluble cellulose derivative powder(s).
 8. The powdery preparation for nasal administration powder according to claim 1, wherein an average particle diameter of the non-water-absorbing and hardly water-soluble cellulose derivative powder(s) is within the range of 5 to 200 μm, and the physiologically active substance and/or the mucolytic cysteine derivative(s) or the combination of the mucolytic cysteine derivative(s) and the nonionic surfactant(s) is/are fixed on the surface of the powder.
 9. The powdery preparation for nasal administration according to claim 1, wherein the content of the physiologically active substance is 0.1 to 80% by weight based on the whole components, the content of the non-water-absorbing and hardly water-soluble cellulose derivative powder(s) is 15 to 99.4% by weight based on the same, and the content of the mucolytic cysteine derivative(s) or the combination of the mucolytic cysteine derivative(s) and the nonionic surfactant(s) is/are 0.5 to 5% by weight based on the same.
 10. The powdery preparation for nasal administration according to claim 1, wherein the cysteine derivative is at least one selected from the group consisting of N-(C₂₋₅ alkanoyl)cysteine, S-(C₁₋₄ alkyl)cysteine, S-(C₂₋₅ carboxy alkyl)cysteine and glutathiones.
 11. The powdery preparation for nasal administration according to claim 1, wherein the mucolytic cysteine derivative is at least one selected from the group consisting of N-acetyl-L-cysteine, S-methyl-L-cysteine, S-ethyl-L-cysteine and S-carboxymethyl-L-cysteine.
 12. The powdery preparation for nasal administration according to claim 1, wherein the nonionic surfactant is at least one selected from the group consisting of a polyoxyethylene-C₁₀₋₁₄ alkyl ether, a polyoxyethylene-(C₆₋₁₀ alkyl-phenyl) ether, a C₆₋₁₀ alkyl-glucose ether and an N-(C₆₋₁₀ alkyl)carbamoyl-C₁₋₄ alkyl-glucose ether.
 13. The powdery preparation for nasal administration according to claim 12, wherein the nonionic surfactant is a nonionic surfactant whose concentration at which 50% of red blood cells are hemolysed is 1% by weight or more.
 14. The powdery preparation for nasal administration according to claim 1, wherein the physiologically active substance is a peptidic physiologically active substance or a polysaceharide physiologically active substance.
 15. A powdery preparation for nasal administration which comprises a physiologically active substance, non-water-absorbing and hardly water-soluble ethyl cellulose powder or cellulose acetate powder and N-acetyl-L-cysteine.
 16. The powdery preparation for nasal administration according to claim 15, wherein physiologically active substance and/or N-acetyl-L-cysteine is/are fixed on the surface of the non-water-absorbing and hardly water-soluble ethyl cellulose powder or the cellulose acetate powder.
 17. The powdery preparation for nasal administration according to claim 1, wherein when said powdery preparation is sprayed or inhaled into a nasal cavity, the physiologically active substance and the mucolytic cysteine derivative(s), or the combination of the mucolytic cysteine derivative(s) and the nonionic surfactant(s) are attached to a mucous membrane of the nasal cavity and retained, and the non-water-absorbing and hardly water-soluble cellulose derivative powder(s) does not absorb mucus of the nasal mucous membrane, and consequently, the physiologically active substance and the mucolytic agent or the combination of the mucolytic cysteine derivative(s) and the nonionic surfactant(s) are dissolved in a minute amount of the mucus, whereby the physiologically active substance and the mucolytic agent or the combination of the mucolytic cysteine derivative(s) and the nonionic surfactant(s) create a locally high concentration solution. 